Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4(+) Th Cells

Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4(+) T helper (Th) cells lacking IRF4 (IRF4(−/−)) are highly sensitive to apoptosis. After infection of IRF4(−/−) mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4(−/−) CD4(+) Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4(−/−) and IRF4(+/+) CD4(+) cells did not increase survival of IRF4(−/−) CD4(+) cells, indicating that the enhanced rate of IRF4(−/−) Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4(+) cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4(−/−) and IRF4(+/+) cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4(−/−) CD4(+) cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4(+) cells against proapoptotic stimuli.